New Approaches to Developing I&I Therapies | Solving the Unmet Need

Session Focus

Fisher opened by framing the dual requirement she wanted the panel to address: how to innovate in inflammation and immunology and how to succeed commercially, since those two things need to move together and frequently do not.

Her opening question to each panelist was where the biggest unmet need actually sits: new targets, better delivery, better patient stratification, or something unnamed.

Matching Therapy to Patient

Niranjana Nagarajan MSc, PhD, whose company originated at Mass General Brigham Ventures and spun out of Brigham and Women’s Hospital, answered that the field needs both new targets and better patient stratification, because the underlying task is matching the therapeutic to the patient.

Her diagnosis of why that is hard: I&I diseases are categorized largely by tissue of origin or clinical specialty. Within any such category sits great diversity in both pathological mechanism and clinical presentation. Targets pursued broadly, attempting to address all the problems, tend not to address enough of them.

The path forward she described is a deeper mechanistic understanding of disease, used both to identify targets specifically relevant to that disease and to identify which patients would benefit.

Fitting the Therapy to the Population

Adrian Ray PhD, working to found a company around a novel approach to a validated target in allergy, located the unmet need in convenience and population fit.

His example was pediatric food allergy, a space where existing therapies may or may not work and which is genuinely difficult. His point was practical rather than pharmacological: giving a child an injection every two days, or an oral therapy every day, does not fit that population regardless of efficacy.

Therapies geared toward the populations with greatest unmet need therefore have to account for how treatment is actually delivered and sustained.

Depleting a Small Set of Bad Actors

Samantha Singer, speaking publicly about her company for the first time as it emerges from stealth, said she is personally on team novel targets, on the grounds that the majority of patients with inflammatory disease lack adequate options.

The company’s origin is an inference from B cell depletion’s impressive results in some indications, which prompted the question of T cell depletion as the next frontier.

The distinction she drew is what makes the approach viable. Rather than depleting an entire cell lineage, the aim is precisely removing a small set of bad actors, delivering efficacy through a targeted approach that can also be quite safe.

The scientific basis comes from founder Steve Greenberg at Massachusetts General Hospital, who identified a small minority population of cells responsible for the vast majority of inflammation seen across many T cell mediated disorders.

The company is now in the clinic with a first-in-class cell-depleting antibody targeting that population, excising highly pathogenic cells while leaving the rest of the immune system wholly unperturbed.

Systemic Versus Local, and the Problem With Reset

Fisher raised the balance between restoring tolerance and suppressing immune response, and whether either should happen systemically or locally.

Nagarajan was direct about the cost of broad systemic immunosuppression. It has substantial use and carries long-term consequences that are less than desirable, sometimes producing problems compounding or worse than the initial diagnosis.

She distinguished two meanings of local. One is delivering a therapeutic to a particular site so it acts there. The other, which is how her company defines it, is looking deeply within the tissue to identify the players specific to inflammation at that site with activity in the disease. That process, which her founder calls autoimmune disease deconstruction, examines tissues to find what is going wrong so treatment can be directed precisely.

Her analogy acknowledged the continued role of broad suppression. With a water leak in the house, the first thing you do is turn off the water main. There is a place for immunosuppressive therapies that bring the immune temperature down. What follows is finding the leak, patching it, and restoring normal water supply. That sequence is the charter for people developing autoimmune therapies: go in more precisely, target what is wrong, and restore normal immune function.

Singer objected to the field’s terminology on substantive grounds. Reset implies wiping the slate clean, which she considers a bad idea with an immune system that has learned a great many lessons over time and should retain them.

Her preferred framing is rebalancing. Certain areas of the body, wherever disease is occurring, have gotten out of balance, and the question is how to give the immune system a chance to rebalance itself toward normalcy rather than starting over.

Key Takeaways

1. I&I diseases are classified by tissue or specialty, which obscures the mechanistic diversity within each category.

2. Broadly aimed targets tend to address some of the problem for many patients rather than enough of it for any.

3. Delivery burden can disqualify an effective therapy, particularly in pediatric populations.

4. Depleting a pathogenic subset rather than a whole lineage is the proposed route to efficacy with acceptable safety.

5. A small minority cell population accounts for most inflammation across many T cell mediated disorders.

6. Systemic suppression remains the equivalent of shutting off the water main, necessary but not the repair.

7. Reset is the wrong word. Rebalancing preserves the immune system’s accumulated learning.